CN109134496B - Method for synthesizing natural product (-) -Porantheridine - Google Patents
Method for synthesizing natural product (-) -Porantheridine Download PDFInfo
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- CN109134496B CN109134496B CN201811255877.XA CN201811255877A CN109134496B CN 109134496 B CN109134496 B CN 109134496B CN 201811255877 A CN201811255877 A CN 201811255877A CN 109134496 B CN109134496 B CN 109134496B
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Abstract
The invention discloses a method for synthesizing a natural product (-) -Porantheridine, which takes a known compound shown in a formula 1 as an initial raw material to synthesize a target molecule through a series of reactions such as tert-butylcarbonyl protection, MHorrer-Wadsworth-Emmons reaction, N-Michael reaction, Pd (II) -catalyzed Wacker oxidation reaction, ring closing reaction and the like. The whole route of the invention is designed uniquely, the reaction conditions in the reaction process are mild, the speed is high, the side reactions are relatively few, the operation is simple and convenient, and the route utilizes conventional chemical reagents, the raw materials are cheap and easy to obtain, and the synthesis cost can be greatly reduced.
Description
Technical Field
The invention relates to a synthetic method of a key intermediate of a natural product, in particular to a synthetic method of a natural product (-) -Porantheridine.
Background
The tricyclic alkaloid (-) -poraNTeridine was isolated in 1972 by j.a. lambrton and colleagues from bush Poranthera corembosa, australia. Its absolute configuration was determined by X-ray analysis and a defined asymmetric synthesis was completed by d.comins and h.huong in 1993.
Alkaloids have been the subject of much pursuit by biologists, pharmacologists and organic synthetic chemists due to their favorable biological activity and complex structure. Poranteridine alkaloid is a natural product molecule with a complex structure. Thus, since their isolation, natural products have been a very attractive synthetic target. To date, synthetic research reports on Porantheridine have been reported by several groups in the world.
The literature reports methods for synthesizing natural products mainly include:
1.(1) a research paper by Goessenger et al in 1980 entitled Stereoselektive synthetic von (. + -.) -Porantreridine; (2) a research paper entitled Asymmetric Synthesis of (-) -Poranteridine published by Comins, DanielL et al in 1993 on the Journal of the American Chemical Society; (3) a research paper entitled effective total synthesis of anticancer (-) -portanthelidine published by David, Marc et al in 1999 on the journal of Organic Chemistry; (4) takahata, Hiroki et al published in 2006 under the title of A new route to trans-2, 6-disubstated piperidine-related analogs using a novel C2-a research paper of symmetric 2, 6-dialylpiperidine carboxylic acid methyl ester; (5) bates, Roderick W et al, 2009 in Journal of Organic Chemistry entitled A formamal synthesis of Porantheridine andan epimer；
(6) In 2010, a research paper entitled Synthetic applications to Racemic porous binder and 8-Epihalosalline via Nitroso Diels-Alder Cycloaddition/Ring-reading metadata Sequence by Pierre Sancibrao et al, J.org.chem.; (7) a research paper entitled Stereogenic Synthesis of Piperidine Alkaloids by Ring-reactive Synthesis/reducing latex Synthesis of Nitroso Diels-Alder Cycloads published by Guillame Vincent et al, chem.Eur.J. in 2013; (8) a research paper entitled Synthesis of the sedum and related metals, A personal perspective, was published by RoderickW et al in Tetrahedron Letters in 2017.
Careful analysis of the route design and methods of total synthesis in the prior art has the disadvantages of long synthesis steps, or single synthesis strategy, difficult operation of individual reactions, expensive reagents and high toxicity.
Disclosure of Invention
The invention aims to solve the problems of long route, high synthesis cost and the like of the existing synthesis method and provides a synthesis method of a full natural product (-) -Poranteridine.
The invention aims to provide a complete synthetic route, and the invention takes a known compound shown in formula 1 as a starting material to synthesize a target molecule through a series of reactions such as tert-butylcarbonyl protection, MHorrer-Wadsworth-Emmons reaction, N-Michael reaction, Wacker oxidation reaction, ring closure reaction and the like with reference to the attached drawing 1 of the specification. The whole route of the invention is designed uniquely, the reaction conditions in the reaction process are mild, the speed is high, the side reactions are relatively few, the operation is simple and convenient, and the route utilizes conventional chemical reagents, the raw materials are cheap and easy to obtain, and the synthesis cost can be greatly reduced.
In order to achieve the purpose, the invention designs a synthetic method of a natural product (-) -Porantheridine, which is characterized by comprising the following steps: a method for synthesizing a natural product (-) -Porantheridine comprises the following steps:
1) byReacting with pent-4-en-1-yl magnesium bromide to obtain
2) To pairCarrying out a tert-butyloxycarbonyl protection reaction to obtain
3) At the temperature of-78 ℃, dichloromethane is used as a solvent,reducing with diisobutylaluminum hydride for 0.5-1 hr to obtain
4)Tetrahydrofuran as solvent, at 0 deg.C under the action of sodium hydride, withBy MHorrer-Wadsworth-Emmons reaction
5)At the temperature of minus 20 ℃, dichloromethane is taken as solvent, and ring closing reaction is carried out under the action of TfOH to obtain
6)By selective reduction to give
7)Performing Wacker oxidation reaction by using N, N-dimethylformamide and water in a ratio of 10:1 as a solvent in the presence of oxygen and palladium chloride and cuprous chloride at room temperature under the catalysis of
8)At the temperature of 0 ℃, under the condition of trifluoroacetic acid, dichloromethane is used as a solvent to carry out Boc removal and ring closing reaction to obtainNamely (-) -poraNTeridine;
the synthetic method of the natural product (-) -Porantheridine comprises the following steps: in the step 1), the reaction conditions are as follows: at 0 ℃ under the protection of nitrogen, andthe tetrahydrofuran solution is added with methyl magnesium bromide dropwise, the solution turns white, stirred for 5 minutes, heated to room temperature and stirred for 0.5 hour at room temperature, cooled to 0 ℃ again, and penta-4-en-1-yl magnesium bromide is slowly added with dropwise into the solution at 0 ℃, heated to room temperature and stirred for reaction for 12 hours, then added with sodium cyanoborohydride at 0 ℃ and injected with glacial acetic acid, and separated and purified after reacting for 45 minutes at room temperature to obtain the compoundThe synthetic method of the natural product (-) -Porantheridine comprises the following steps: in the step 2), the conditions of the tert-butyloxycarbonyl protection reaction are as follows: at room temperature under nitrogenUnder protection, handleDissolving in tetrahydrofuran solution, adding 4-dimethylamino pyridine, stirring for 0.5 hr, dropping di-tert-butyl dicarbonate at 0 deg.C, reacting at room temperature for 18 hr, separating and purifying to obtainThe synthetic method of the natural product (-) -Porantheridine comprises the following steps: in the step 3), the carbonyl reduction conditions are as follows: under the protection of nitrogen at room temperature,dissolving the mixture in dichloromethane solution, cooling to-78 ℃, slowly dropping diisobutylaluminum hydride into the solution at the temperature, reacting at-78 ℃ for 0.5-1 hour, and separating and purifying to obtain the final productThe synthetic method of the natural product (-) -Porantheridine comprises the following steps: in the step 4), the mixture is heated at room temperature under the protection of nitrogenDissolving in tetrahydrofuran solution, adding sodium hydride at 0 deg.C, stirring at room temperature for 1 hr, dissolving in tetrahydrofuran at 0 deg.CSlowly adding dropwise into the above solution, heating to room temperature, reacting for 2.5 hr under stirring, separating and purifying to obtainThe synthetic method of the natural product (-) -Porantheridine comprises the following steps: in the step 5), the mixture is heated at room temperature under the protection of nitrogenDissolved in dichloro-chlorineAdding TfOH dissolved in dichloromethane dropwise into methane solution at-20 deg.C, reacting at the temperature for 5 hr, separating and purifying to obtainThe synthetic method of the natural product (-) -Porantheridine comprises the following steps: in step 6), the mixture is heated at room temperature under the protection of nitrogenDissolving in methanol, cooling to 0 deg.C, adding sodium borohydride at the temperature, reacting at room temperature for 1-1.5 hr, separating and purifying to obtainThe synthetic method of the natural product (-) -Porantheridine comprises the following steps: in step 7), mixingDissolving in N, N-dimethylformamide: adding palladium chloride and cuprous chloride into 10:1 water solution, reacting at room temperature under the condition of full oxygen for 24 hr, filtering, separating and purifying to obtainThe synthetic method of the natural product (-) -Porantheridine comprises the following steps: in step 8), mixingDissolving in dichloromethane solution, cooling to 0 deg.C, slowly adding trifluoroacetic acid dropwise at the temperature, reacting at room temperature for 2 hr, separating and purifying to obtainNamely (-) -Porantheridine.
The invention has the beneficial effects that:
1. the design of the whole synthesis route is unique, the (-) -Poranteridine is singly selectively synthesized, the speed is high, the side reaction is relatively less, and the product yield is high;
2. the conventional chemical reagent is utilized in the route, the raw materials and the reagent are cheap and easy to obtain, and the production cost can be greatly reduced;
3. the synthesis route has simple and reasonable design, simple and convenient operation process, mild reaction conditions in the reaction process, less linear steps and suitability for industrial preparation.
Drawings
FIG. 1 is a flow diagram of the reaction of the present invention.
Detailed Description
In order to better explain the present invention, the present invention is further described in detail with reference to the following specific examples. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
Example 1
As described in the specification and attached figure 1
1) Synthesis of compounds of formula 2:
dropwise adding methyl magnesium bromide (47.4mL) into a tetrahydrofuran (210mL) solution of a compound (5.06g, 44.76mmol) of the formula 1 at 0 ℃ under the protection of nitrogen, enabling the solution to become white and turbid, returning to room temperature, stirring at room temperature for 30 minutes, cooling to 0 ℃ again, dropwise adding pent-4-en-1-yl magnesium bromide (70.6mL) at the temperature, and stirring at room temperature for 12 hours; to the mixture was added a saturated sodium bicarbonate solution (40mL), extracted with ethyl acetate (3 × 80mL), the resulting organic phases were combined, washed with saturated brine and dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the organic solvent, and the resulting crude product was separated and purified by flash column chromatography (methanol: dichloromethane ═ 1:60) to give a white liquid, i.e., the compound of formula 2 (5.32g, 71%).
2) Synthesis of Compounds of formula 3
The compound of formula 2 (2.26g,13.52mmol) was dissolved in tetrahydrofuran (65mL) at room temperature under nitrogen, 4-dimethylaminopyridine (1.65g,13.52mmol) was added, and after stirring for 30 minutes, di-tert-butyl dicarbonate (1.17mL,5.10mmol) was added dropwise at 0 ℃. To the mixture was added a saturated ammonium chloride solution (20mL), extracted with ethyl acetate (3 × 80mL), and the resulting organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to remove the organic solvent to give a crude product, which was then separated and purified by flash column chromatography (ethyl acetate: petroleum ether ═ 1:9) to give a compound of formula 3 (3.40g, 94%) as a yellow oily liquid.
3) Synthesis of Compound of formula 4
A solution of the compound of formula 3 (0.7g,2.62mmol) in dichloromethane (26mL) is cooled to-78 ℃ under the protection of nitrogen at room temperature, then 1.5M diisobutylaluminum hydride (4.4mL) is slowly added dropwise and reacted at this temperature for 0.5 to 1 hour, then methanol (5mL) is added and stirred at-78 ℃ for 15 minutes, then a saturated solution of potassium sodium tartrate (10mL) is added, warmed to room temperature and stirred at room temperature for 1 hour, the resulting mixed system is extracted with dichloromethane (3 × 80mL), the resulting organic phases are combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the organic solvent, and the resulting crude product is separated and purified by flash column chromatography (ethyl acetate: petroleum ether ═ 1:10) to give a colorless oily liquid, i.e. the compound of formula 4 ((0.63g, 89%).
4) Synthesis of Compounds of formula 6
Dissolving the compound of formula 5 (4.3g,22mmol) in tetrahydrofuran (120mL) at room temperature under the protection of nitrogen, adding sodium hydride (0.88g,22mmol) at 0 ℃, stirring at room temperature for 1 hour, adding the compound of formula 4 (2.96g,10.99mmol) in tetrahydrofuran (30mL) to the above mixture at 0 ℃, stirring at room temperature for reaction for 2.5 hours, adding saturated ammonium chloride solution (20mL) to the mixture, extracting with dichloromethane (3 × 30mL), combining the obtained organic phases, washing with saturated brine, drying the organic phase with anhydrous sodium sulfate, then concentrating under reduced pressure to remove the organic solvent to obtain a crude product, and then separating and purifying the obtained crude product by flash column chromatography (ethyl acetate: petroleum ether ═ 1:10) to obtain a colorless oily liquid, namely the compound of formula 6 (3.03g, 82%).
5) Synthesis of Compounds of formula 7
Dissolve the compound of formula 6 (182mg,0.54mmol) at room temperature under nitrogen protectionDichloromethane (54mL), cooled to-20 deg.C, TfOH (0.54mmol, CH) was added2Cl20.2M) was added, and after stirring at-20 ℃ for 5 hours, the reaction was quenched by addition of saturated sodium bicarbonate solution (40 mL). The resulting mixed system after quenching was extracted with dichloromethane (3 × 80mL), the resulting organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to remove the organic solvent, and the resulting crude product was separated and purified by flash column chromatography (ethyl acetate: petroleum ether ═ 1:30) to give a compound of formula 7 (141mg, 78%) as a colorless liquid.
6) Synthesis of Compounds of formula 8
Dissolving the compound of formula 7 (1.42mg,4.21mmol) in methanol solution (21mL) at room temperature under the protection of nitrogen, cooling to 0 ℃, adding sodium borohydride solid (0.57g,15.16mmol) at 0 ℃, then stirring at room temperature for 30 minutes, adding saturated ammonium chloride solution (30mL) to the mixture, extracting with dichloromethane (3 × 30mL), combining the obtained organic phases, washing with saturated brine, drying the organic phase with anhydrous sodium sulfate, then removing the organic solvent by concentration under reduced pressure to obtain a crude product, and then separating and purifying the obtained crude product by flash column chromatography (ethyl acetate: petroleum ether ═ 1:20) to obtain a colorless oily liquid, namely the compound of formula 8 (1.11g, 78%).
7) Synthesis of Compounds of formula 9
After a compound of formula 8 (0.85g,2.50mmol) was dissolved in a solution of N, N-dimethylformamide/water (10:1) (55mL) at room temperature under protection of oxygen, palladium chloride (0.18g,1.0mmol) and cuprous chloride (1.24g,12.5mmol) were added, and the mixture was reacted at room temperature for 24 hours, the mixture was filtered through celite, extracted with dichloromethane (3 × 60mL), the resulting organic phases were combined, washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, and the organic solvent was removed by concentration under reduced pressure to obtain a crude product, which was then separated and purified by flash column chromatography (ethyl acetate: petroleum ether ═ 1:3) to obtain a colorless liquid, i.e., a compound of formula 9 (0.74g, 83%).
8) (-) -Poranteridine Synthesis
Dissolving a compound (62mg,0.17mmol) of formula 8 in dichloromethane solution (11mL) at room temperature under the protection of oxygen, slowly dropwise adding trifluoroacetic acid (1.24mL) at 0 ℃, stirring for 2 hours at room temperature, then using a vacuum rotary evaporator to remove instable substances in the mixed system, adding 20mL of saturated sodium bicarbonate solution into the rest mixed system, extracting with dichloromethane (3X 40mL), combining the obtained organic phases, filtering with diatomite, washing with saturated common salt water, drying with anhydrous sodium sulfate, then concentrating under reduced pressure to remove the organic solvent to obtain a crude product, and separating and purifying the obtained crude product by flash column chromatography (methanol: dichloromethane ═ 1:10) to obtain a colorless liquid, namely (-) -Poranteridine ((35mg, 85%).
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included therein.
Claims (9)
1. A method for synthesizing a natural product (-) -Poranteridine is characterized by comprising the following steps:
1) byReacting with pent-4-en-1-yl magnesium bromide to obtain
2) To pairCarrying out a tert-butyloxycarbonyl protection reaction to obtain
3) At the temperature of-78 ℃, dichloromethane is used as a solvent,reducing with diisobutylaluminum hydride for 0.5-1 hr to obtain
4)Tetrahydrofuran as solvent, at 0 deg.C under the action of sodium hydride, withBy means of Horner-Wadsworth-Emmons reaction to obtain ring opening
5)At the temperature of minus 20 ℃, dichloromethane is taken as solvent, and ring closing reaction is carried out under the action of TfOH to obtain
6)By selective reduction to give
7)Performing Wacker oxidation reaction by using N, N-dimethylformamide and water in a ratio of 10:1 as a solvent in the presence of oxygen and palladium chloride and cuprous chloride at room temperature under the catalysis of
8)At the temperature of 0 ℃, under the condition of trifluoroacetic acid, dichloromethane is used as a solvent to carry out Boc removal and ring closing reaction to obtainNamely (-) -Porantheridine.
2. The method for synthesizing the natural product (-) -Porantheridine according to claim 1, characterized in that: in the step 1), the reaction conditions are as follows: at 0 ℃ under the protection of nitrogen, andthe tetrahydrofuran solution is added with methyl magnesium bromide dropwise, the solution turns white, stirred for 5 minutes, heated to room temperature and stirred for 0.5 hour at room temperature, cooled to 0 ℃ again, and penta-4-en-1-yl magnesium bromide is slowly added with dropwise into the solution at 0 ℃, heated to room temperature and stirred for reaction for 12 hours, then added with sodium cyanoborohydride at 0 ℃ and injected with glacial acetic acid, and separated and purified after reacting for 45 minutes at room temperature to obtain the compound
3. The method for synthesizing the natural product (-) -Porantheridine according to claim 1, characterized in that: in the step 2), the conditions of the tert-butyloxycarbonyl protection reaction are as follows: under the protection of nitrogen at room temperatureDissolving in tetrahydrofuran solution, adding 4-dimethylamino pyridine, stirring for 0.5 hr, dropping di-tert-butyl dicarbonate at 0 deg.C, reacting at room temperature for 18 hr, separating and purifying to obtain
4. The method for synthesizing the natural product (-) -Porantheridine according to claim 1, characterized in that: in the step 3), the carbonyl reduction conditions are as follows: under the protection of nitrogen at room temperature,dissolving the mixture in dichloromethane solution, cooling to-78 ℃, slowly dropping diisobutylaluminum hydride into the solution at the temperature, reacting at-78 ℃ for 0.5-1 hour, and separating and purifying to obtain the final product
5. The method for synthesizing the natural product (-) -Porantheridine according to claim 1, characterized in that: in the step 4), the mixture is heated at room temperature under the protection of nitrogenDissolving in tetrahydrofuran solution, adding sodium hydride at 0 deg.C, stirring at room temperature for 1 hr, dissolving in tetrahydrofuran at 0 deg.CSlowly adding dropwise into the above solution, heating to room temperature, reacting for 2.5 hr under stirring, separating and purifying to obtain
6. The method for synthesizing the natural product (-) -Porantheridine according to claim 1, characterized in that: in the step 5), the mixture is heated at room temperature under the protection of nitrogenDissolving in dichloromethane solution at-20 deg.CAdding TfOH dissolved in dichloromethane dropwise, reacting for 5 hours at the temperature, separating and purifying to obtain
7. The method for synthesizing the natural product (-) -Porantheridine according to claim 1, characterized in that: in step 6), the mixture is heated at room temperature under the protection of nitrogenDissolving in methanol, cooling to 0 deg.C, adding sodium borohydride at the temperature, reacting at room temperature for 1-1.5 hr, separating and purifying to obtain
8. The method for synthesizing the natural product (-) -Porantheridine according to claim 1, characterized in that: in step 7), mixingDissolving in N, N-dimethylformamide: adding palladium chloride and cuprous chloride into 10:1 water solution, reacting at room temperature under the condition of full oxygen for 24 hr, filtering, separating and purifying to obtain
9. The method for synthesizing the natural product (-) -Porantheridine according to claim 1, characterized in that: in step 8), mixingDissolving in dichloromethane solution, cooling to 0 deg.C, slowly adding trifluoroacetic acid dropwise at the temperature, reacting at room temperature for 2 hr, and separatingIs obtained by pureNamely (-) -Porantheridine.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105294725A (en) * | 2015-11-03 | 2016-02-03 | 江西科技师范大学 | Asymmetric synthesis method for natural products Aculeatins A, B, D and 6-epi-Aculeatin D |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105294725A (en) * | 2015-11-03 | 2016-02-03 | 江西科技师范大学 | Asymmetric synthesis method for natural products Aculeatins A, B, D and 6-epi-Aculeatin D |
Non-Patent Citations (8)
| Title |
|---|
| A Formal Synthesis of Porantheridine and an Epimer;Roderick W. Bates，等;《J. Org. Chem.》;20091125;第74卷;第9460-9465页 * |
| A new route to trans-2,6-disubstituted piperidine-related alkaloids using a novel C2-symmetric 2,6-diallylpiperidine carboxylic acid methyl ester;Hiroki Takahata，等;《Org. Biomol. Chem.》;20061231;第4卷;第1587-1595页 * |
| Asymmetric Synthesis of (-)-Porantheridine;Daniel L. Comins，等;《J. Am. Chem. Soc.》;19931231;第115卷;第8851-8852页 * |
| Intramolecular amidocyclopropanation reactions using diethoxymethyl-functionalised lactams as organozinc carbenoid precursors;Laure Jerome，等;《Tetrahedron Letters》;20090418;第50卷;第3709-3712页 * |
| Stereodivergent Synthesis of Piperidine Alkaloids by Ring-Rearrangement Metathesis/Reductive Lactam Alkylation of Nitroso Diels–Alder Cycloadducts;Guillaume Vincent，等;《Chem. Eur. J.》;20130605;第19卷;第9358-9365页 * |
| Stereoselective synthesis of (±)-porantheridine and (±)-porantherilidine;Edda Gossinger;《Monatshefte fur Chemie》;19801231;第111卷;第783-787页 * |
| Synthesis of the sedum and related alkaloids: A personal perspective;Roderick W. Bates;《Tetrahedron Letters》;20171208;第59卷;第559-567页 * |
| 天然环酯肽Obyanamide的全合成;王晓季，等;《有机化学》;20071231;第27卷(第8期);第1007-1012页 * |
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